Recent experiments suggest the presence of two types of sigma "opiate" binding sites, a phencyclidine-sensitive site (sigma p) and a haloperidol-sensitive site (sigma H). The sigma h site has a unique distribution in the brain and is especially concentrated in many brain regions associated with movement and posture. Of these, the red nucleus, a sizeable nucleus in the midbrain tegmentum, is of special interest because it is rich in sigma h receptors but largely lacking in other known receptor types. It is possible that the sigma h site underlies the effects of various psychotomimetic opioids. However, binding experiments that demonstrated the existence of sigma h sites do not assure that the entity is a functional receptor. Therefore, the proposed research aims to establish its functional significance. Early studies employ binding techniques to verify the specificity of two apparently selective sigma h ligands, di-o-tolyl-guanidine (DTG) and (+)- pentazocine. Then, in vivo approaches are used to address the functional significance of the sigma h binding site. The proposed studies use microinjection/behavior and microiontophoresis/unit- recording approaches focusing on the red nucleus to avoid, to the greatest possible extent, interactions of the ligands with unwanted receptor types. In these experiments the structure- activity relationships will be examined as will interactions between various sigma h ligands. In addition, chronic administration of sigma h ligands will be used in attempts to up- or down- regulate the sigma h receptor. If the sigma h binding site is a functioning biological receptor it should be possible to regulate its expression, and the efficacy of sigma h ligands should be affected concomitantly. In addition, a correlation between the binding affinity of various ligands and their in vivo potency would suggest biological significance. Finally, antagonism between certain pairs of ligands would also suggest biological significance. The proposed studies should, therefore, provide several bases for judging the functional relevance of the sigma h receptor and lay a foundation for future investigations of the mechanism of action of the sigma h ligands.